Higher neutrophil infiltration mediated by osteopontin is a likely contributing factor to the increased susceptibility of females to alcoholic liver disease
Higher neutrophil infiltration mediated by osteopontin is a likely contributing factor to the increased susceptibility of females to alcoholic liver disease
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DOI：
10.1002/path.1917
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发表时间：
2006-03-01
影响因子：
7.3
通讯作者：
Ramaiah, SK
中科院分区：
文献类型：
--
作者：
Banerjee, A;Apte, UM;Ramaiah, SK
酒精性肝病(ALD)在美国是一个主要的公共卫生问题，众所周知，女性更容易患ALD。然而，女性对ALD易感性增加的确切机制并不完全清楚。本研究基于一种假设，即骨桥蛋白(OPN)是一种基质细胞蛋白，可能是酒精性脂肪性肝炎(ASH)期间女性中性粒细胞募集增加的可能因素。给雄性和雌性SD大鼠喂饲含乙醇(Etoh)的Lieber-DeCarli饲料6周，然后单次注射脂多糖(LPS，10 mg/kg，ip)，造成大鼠ASH。通过血浆转氨酶升高并经苏木素和伊红染色的肝脏切片证实的肝脏损伤，显示女性ASH模型的肝脏损伤类似于男性的25倍。雌雄大鼠均有明显的脂肪变性、坏死和中性粒细胞浸润，但雌鼠在注射内毒素后2 h即可观察到中性粒细胞坏死灶。乙醇+脂多糖处理的雌性大鼠肝脏中性粒细胞浸润与裂解的骨桥蛋白(COPN)和未裂解的OPN的表达高于雄性大鼠。在ASH模型中，OPN的分泌主要定位于胆管上皮，女性的OPN mRNA明显高于男性。在体内，在腹膜炎大鼠模型中，以及通过中和OPN(NOPN)抗体实验，进一步证实了OPN吸引中性粒细胞的能力。NOPN抗体对肝中性粒细胞的侵袭有明显的抑制作用(接近50%)。流式细胞仪检测显示OPN介导的CD11b中性粒细胞黏附分子表达上调。综上所述，这些数据提示OPN在肝脏的高表达可能是肝脏中性粒细胞在ASH期间较高和早期的浸润使女性更易患ALD的原因。版权所有(C)2006年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Alcoholic liver disease (ALD) is a major public health problem in the United States and women are known to be more susceptible to ALD. However, the precise mechanism for increased susceptibility of females to ALD is not completely understood. The present study is based on the hypothesis that induction of osteopontin (OPN), a matricellular protein, is the likely contributing factor for higher neutrophil recruitment in females during alcoholic steatohepatitis (ASH). ASH was induced in male and female Sprague-Dawley rats by feeding them a Lieber-DeCarli diet containing ethanol (EtOH) for 6 weeks, followed by a single injection of lipopolysaccharide (LPS, 10 mg/kg, ip). Liver injury, measured by plasma transaminase elevations and confirmed by haematoxylin and eosin-stained liver sections, revealed similar to 25-fold higher liver injury in the female ASH model compared with the males. Although steatosis, necrosis, and neutrophil infiltration were evident in both male and female rats, hepatic neutrophilic necrotic foci were noted as early as 2 h after LPS injection in the EtOH-treated female rats. Hepatic neutrophil infiltration correlated with higher expression of cleaved (cOPN) and uncleaved OPN in the EtOH + LPS-treated female rats compared with the males. OPN secretion was localized predominantly in the biliary epithelium and females had significantly higher OPN mRNA than their male counterparts in the ASH model. The ability of OPN to attract neutrophils was further confirmed in vivo, in a peritonitis rat model, and by neutralizing OPN (nOPN) antibody experiments. Hepatic neutrophil infiltration was largely inhibited (similar to 50%) by nOPN antibody. Flow cytometry experiments revealed OPN-mediated up-regulation of the CD11b neutrophil adhesion molecule. In conclusion, these data suggest that higher hepatic expression of OPN is the likely reason for higher and early hepatic neutrophil infiltration making females more susceptible to ALD during ASH. Copyright (c) 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.